It has become common to utilize implantable medical devices for a wide variety of medical conditions, e.g., drug infusion and hemodialysis access. However, medical device implantation often comes along with the risk of infections (1), inflammation (2), hyperplasia (3), coagulation (4). It is therefore important to design such materials to provide enhanced biocompatibility. Biocompatibility is defined as the ability of a material to perform with an appropriate host response in a specific application. The host relates to the environment in which the biomaterial is placed and will vary from being blood, bone, cartilage, heart, brain, etc. Despite the unique biomedical related benefits that any particular group of polymers may possess, the materials themselves, once incorporated into the biomedical device, may be inherently limited in their performance because of their inability to satisfy all the critical biocompatibility issues associated with the specific application intended. For instance while one material may have certain anti-coagulant features related to platelets it may not address key features of the coagulation cascade, nor be able to resist the colonization of bacteria. Another material may exhibit anti-microbial function but may not be biostable for longterm applications. The incorporation of multi-functional character in a biomedical device is often a complicated and costly process which almost always compromises one polymer property or biological function over another, yet all blood and tissue contacting devices can benefit from improved biocompatibility character. Clotting, toxicity, inflammation, infection, immune response in even the simplest devices can result in death or irreversible damage to the patient. Since most blood and tissue material interactions occur at the interface between the biological environment and the medical device, the make-up of the outer molecular layer (at most the sub-micron layer) of the polymeric material is relevant to the biological interactions at the interface. This is a particularly challenging problem for biodegradable polymer systems when a continuous exposure of new surfaces through erosion of the bulk polymer requires a continuous renewal of biocompatible moieties at the surface.
Bioactive agents containing polymer coatings have been developed to improve the biocompatibility of medical device surfaces. Patnaik et al. (5) described a method of attaching bioactive agents, such as heparin (an anti-coagulant) to polymeric substrates via a hydrophilic, isocyanate/amine-terminated spacer in order to provide a coating of the bio-active material on the medical device. The investigator found that the bioactive agent's activity was achieved when the spacer group had a molecular weight of about 100-10,000 daltons. But most preferably that is of 4000 daltons. Unfortunately, such a material would only be applicable for substrates which were not intended to under go biodegradation and exchange with new tissue integration since the heparin in limited to surface and does not form the bulk structure of the polymer chains.
Another example of biomaterial design relates to infection control. In the last decade, a number of strategies have been used in attempts to solve problems such as those associated with medical device infection. One approach is to provide a more biocompatible implantable device to reduce the adhesion of bacteria. Silver coated catheters have been used to prevent exit site infections associated with chronic venous access (6) and peritoneal dialysis (7). However, longterm studies have failed to demonstrate a significant reduction in the number or severity of exit site infections. In addition, bacterial resistance to silver can develop over time and carries with it the risk of multiple antibiotic resistances (8).
Since bacteria adhesion is a very complex process, complete prevention of bacteria adhesion is difficult to achieve with only a passive approach. There remains a need for local controlled drug delivery. The advantages for the latter approach include 1) a high and sustained local drug concentration can be achieved without the systemic toxicity or side effects which would be experienced from systemic doses sufficient to obtain similar local drug concentration; 2) high local drug concentration can be attained, even for agents that are rapidly metabolized or unstable when employed systemically; 3) some forms of site-specific delivery have the potential to establish and maintain local drug action, either by preventing its efflux from the arterial wall or by using vehicles or agents that have a prolonged duration of action; 4) it gives the potential for designing a smart drug delivery system, which can be triggered to start the release and/or modulate the rate of release according to the infection status.
Methods for obtaining compositions which contain drugs and polymers in a composite form to yield bioactive agent release coatings are known. For example, Chudzik et al. (9) formulated a coating composite that contained a bioactive agent (e.g. a drug) and two polymers, i.e., poly(butyl methacrylate) and poly(ethylene-co-vinyl acetate). The coating formed from the above formulation provided good durability and flexibility as well as significant drug release, which could be particularly adapted for use with devices that undergo significant flexion and/or expansion in the course of their delivery and/or use, such as stents and catheters. These approaches have the benefit of localized delivery at high drug concentration, but are unable to keep a sustained and controlled release of drug for long periods. Ragheb et al. (10) found a method for the controlled release of a bioactive agent from polymer coatings. Wherein, two coating layers of polymer were applied to a medical device. The first layer of the device is an absorbent material such as parylene derivatives. Drug or bioactive agent is deposited over at least a portion of this layer. The second biocompatible polymer layer on top of the drug and the first layer must be porous. The polymer is applied by vapor deposition or by plasma deposition. Since the drug release mechanism is totally controlled by porous sizes, making a suitable porous size distribution in the second layer in order to satisfy the required release model is often a technical challenge. As well, this type of system requires multiple processing steps which increases production cost and adds to the need for QA/QC steps.
In addition to the traditional diffusion-controlled delivery systems described in the above references, there exist several more sophisticated in situ drug delivery polymers which can alter the efficacy of drugs by improving target delivery and changing the control parameters of the delivery rate. These include biodegradable hydrogels (11), polymeric liposomes (12), bioresorbable polymers (13) and polymer drugs (14-16). Polymer drugs contain covalently attached pharmaceutical agents on the polymer chain as pendent groups, or even incorporated into the polymer backbone. For example, Nathan et al (17) conjugated penicillin V and cephradine as pendant antibiotics to polyurethanes. Their work showed that hydrolytically labile pendant drugs were cleaved and exhibited antimicrobial activities against S. aureus, E. faecalis and S. pyogenes. 
Ghosh et al. (18) coupled nalidixic acid, a quinolone antibiotic, in a pendant manner to an active vinyl molecule. These vinyl groups can then be polymerized to generate a polymer with pendent antibiotics on each monomer. However, having such pendant groups will dramatically alter the physical structure of the polymer. A better strategy would be to have the drugs within the linear backbone portion of the polymer. In in-vivo hydrolysis studies they reported a 50% release of drug moieties over the first 100 hours. This quinolone drug has been shown to be effective against gram negative bacteria in the treatment of urinary track infections, however chemical modifications of the latter (e.g. ciprofloxacin, norfloxacin and others) have a wider spectrum of activity. More recent work on the conjugation of norfloxacin to mannosylated dextran has been reported. This was driven in an effort to increase the drug's uptake by cells, enabling them to gain faster access to micro-organisms (19). The studies showed that norfloxacin could be released from a drug/polymer conjugate by enzyme media and in vivo studies, the drug/polymer conjugate was effective against Mycobacterium tuberculosis residing in liver (20). In the system, norfloxacin was attached pendant to sequences of aminoacids which permitted its cleavage by the lysosomal enzyme, cathepsin B.
Santerre (13a) describes the synthesis and use of novel materials to which when added to polymers converts the surface to have bioactive properties, while leaving the bulk properties of the polymer virtually intact. Applications are targeted for the biomedical field. These materials are oligomeric fluorinated additives with pendant drugs that are delivered to the surface of bulk polymers during processing by the migration of the fluorine groups to the air/polymer interface. These materials can deliver a large array of drugs, including anti-microbials, anti-coagulants and anti-inflammatory agents, to the surface. However modification is limited to the surface. This becomes a limitation in a biodegradable polymer which may require sustained activity throughout the bio-erosion process of the polymer.
Santerre and Mittleman (14) teach the synthesis of polymeric materials using pharmacologically-active agents as one of the co-monomers for polymers. Wherein, 1,6-diisocynatohexane and/or 1,12-diisocyanatododecane monomers or their oligomeric molecules are reacted with the antimicrobial agent, ciprofloxacin, to form drug polymers. The pharmacologically-active compounds provide enhanced long term antiinflammatory, anti-bacterial, anti-microbial and/or anti-fungal activity. However, since the reactivities of the carboxylic acid group and the secondary amine group of ciprofloxacin with the isocyanate groups are different, the reaction kinetics become challenging. As well, formulations must be selective in order to minimize strong van der Waals interactions between the drug components and hydrogen bonding moieties of the polymer chains since this can delay the effective release of drug. Hence, an improvement over the latter system are biomonomers made up of the drugs and agents which, without being bound by theory, would ensure a less restricted access of the drug during hydrolysis of the polymer, as well as providing more uniform chemical function for reaction with the isocyanate groups or other monomer reagents.